Creatine (Cr), or 2-(carbamimidoyl-methyl-amino) acetic acid, is a naturally occurring nitrogenous organic acid synthesized in the liver of vertebrates and helps to supply energy to muscle and nerve cells. Creatine is synthesized from the amino acids arginine, methionine, and glycine through a two-step enzymatic process involving GAMT (guanidinoacetate N-methyltransferase, also known as glycine amidinotransferase) by methylation of guanidoacetate using S-adenosyl-L-methionine (SAM) as the methyl donor. Guanidoacetate is formed in the kidneys from the amino acids arginine and glycine. Once made in the liver or acquired through digestion, creatine is stored in cells including muscle and brain cells.
Several forms of the enzyme creatine (phospho)kinase (CPK or CK), exist but the most ubiquitous form of the enzyme resides in the mitochondrion, where it produces phosphocreatine from mitochondrially-generated ATP and imported creatine from the cytosol. CPK catalyzes the transfer of the phosphate from ATP to the guanidinium of creatine, forming creatine phosphate (PCr). The reaction is reversible, such that when energy demand is high (e.g., during muscle exertion or brain activity), CPK can dephosphorylate creatine phosphate and transfer the phosphate back to ADP forming ATP. This enables creatine to act as an energy storage molecule where phosphate can be stored independently of ATP.
Perturbed mitochondrial function can lead to ATP depletion, resulting in significant physiological problems. One potential method of addressing ATP depletion is to increase phosphocreatine (PCr) stores, for example by administering creatine which can be phosphorylated by CPK. Several forms of CPK exist but the most ubiquitous form of the enzyme resides in the mitochondrion, where it produces phosphocreatine from mitochondrially-generated ATP and creatine from the cytosol. However, creatine transport to the mitochondrion is an energy requiring process. Accordingly, a need remains for creatine analogs targeted to the mitochondrion to circumvent the energy loss associated with endogenous creatine transport and to provide creatine at the subcellular location of creatine action.
Skin Aging is the condition by which skin undergoes progressive degenerative change, including both structural and physiologic changes, which occur from intrinsic aging and extrinsic damage and environmental insult, including over exposure to solar radiation. Farage, Miranda A., et al. “Clinical implications of aging skin: cutaneous disorders in the elderly.” American journal of clinical dermatology 10.2 (2009): 73-86. Pathologic changes include: delayed cellular migration and proliferation, loss of elasticity, decreased tensile strength, fragile, thin skin which renders it more susceptible to injury, delayed collagen remodeling, reduced epidermal hydration and greater susceptibility to solar radiation. Age and the exposure to sun are risk factors in contracting melanoma.
Creatine increase athletic performance as well as cognitive abilities in the elderly. Juhn, Mark S., and Maek Tarnopolsky. “Oral creatine supplementation and athletic performance: a critical review.” Clinical journal of sport medicine: official journal of the Canadian Academy of Sport Medicine 8.4 (1998): 286; and McMorris, Terry, et al. “Creatine supplementation and cognitive performance in elderly individuals.” Aging, Neuropsychology, and Cognition 14.5 (2007): 517-528. Creatine has also been shown in combination with Folic acid to increase collagen expression in fibroblasts, and a subsequent increase dermal firmness. Fischer, Frank, et al. “Folic acid and creatine improve the firmness of human skin in vivo.” Journal of Cosmetic Dermatology 10.1 (2011): 15-23; Knott, Anja, et al. “A novel treatment option for photoaged skin.” Journal of Cosmetic Dermatology 7.1 (2008): 15-22; and Shamban, Ava T. “Current and new treatments of photodamaged skin.” Facial Plastic Surgery 11.5 (2009): 337. Creatine by itself may slow down the mutagenesis that is one of the hallmarks of photoaging. Berneburg, Mark, et al. “Creatine supplementation normalizes mutagenesis of mitochondrial DNA as well as functional consequences.” Journal of investigative dermatology 125.2 (2005): 213-220.
During the treatment of cancer, many patients are administered Epidermal Growth Factor Receptor inhibitors, such as antibodies (e.g. cetuximab, panitumumab, or the like) or kinase inhibitors (e.g. gefitinib, erlotinib, or the like), and a large percentage of this patient population develop acne like skin eruptions. Segaert, Siegfried, and Eric Van Cutsem. “Clinical signs, pathophysiology and management of skin toxicity during therapy with epidermal growth factor receptor inhibitors.” Annals of Oncology 16.9 (2005): 1425-1433; and Agero, Anna Liza C., et al. “Dermatologic side effects associated with the epidermal growth factor receptor inhibitors.” Journal of the American Academy of Dermatology 55.4 (2006): 657-670.
76% of physicians reported delaying treatment of EGFRi at some point during therapy because of skin rash and 32% of physicians reported discontinuing EGFRi treatment altogether due to skin rash. Other anti-cancer agents such as Gemcitabine and Temozolomide may be used in combination with EGFR inhibitors or in combinations with other chemotherapeutic agents, and may also induce skin rash.
Topical glucocorticoids are highly effective for the treatment of inflammatory skin diseases and conditions. Their long-term use, however, is often accompanied by severe and partially irreversible adverse effects, with skin atrophy being the most prominent limitation. Telangiectasia and striae can appear within 2 to 3 days of starting daily application, the greatest potential occurring when the application is occluded or when the preparation is applied to fragile skin. Skin atrophy consists of a reduction in epidermal and dermal thickness, regression of the sebaceous glands, subcutaneous fat loss, and muscle-layer atrophy. These changes are typically observed following 2 to 3 weeks of moderate- to high-potency topical corticosteroid use. A single application of a very potent topical steroid can cause an ultrasonographically detectable decrease in skin thickness that lasts up to 3 days. Even low-potency topical steroids can cause slight skin atrophy that often reverses upon discontinuation of the drugs. Atrophy and striae are of concern on areas of the skin with high permeability, such as the face and intertriginous areas, but these adverse events can occur anywhere, especially after long-term use of moderate- or high-potency topical corticosteroids. While mild atrophy and telangiectasia might be reversible upon discontinuation of corticosteroids, overtly visible changes in skin texture and striae are considered permanent manifestations of corticosteroid-induced atrophy and are resistant to treatment.
There is a need to improve the function, texture, feel and appearance of the skin of a patient having wrinkles. There also exists a need to prevent, alleviate or diminish the negative side effects of cancer treatments on the patients' skin in order to increase said patients ability to tolerate prescribed anti-cancer treatments and concomitantly increase his or her quality of life. The present invention addresses these needs and others.